Specific and rapid induction of the proapoptotic protein Hrk after growth factor withdrawal in hematopoietic progenitor cells

Hrk is a newly described proapoptotic member of the Bcl-2 family that is ma inly expressed in hematopoietic tissues and cultured neurons. In this study we have examined the expression and activity of Hrk in hematopoietic proge nitors. To address these issues, we used 3 growth factor-dependent murine h ematopoietic cell lines, HCD-57, FDCP-Mix, and FL5.12, The expression of Hr k was undetectable in cells cultured with growth factors, but it was rapidl y up-regulated on growth factor withdrawal. In contrast, the expression of Bcl-x(L) decreased and that of proapoptotic Bar, Bad, and Bak was unchanged or down-regulated after removal of growth factors. This pattern of express ion correlated with the induction of apoptosis. Hrk was also up-regulated i n human cell lines and in bone marrow-derived CD34(+) cells cultured in the absence of growth factors. In addition, the levels of Hrk were up-regulate d after treatment with the chemotherapeutic drug etoposide, Expression of p rosurvival Bct-x(L) or Bcl-2 proteins blocked the induction of Hrk, Hrk was induced in FDCP-Mix cells treated with ionomicin in the presence of IL-3, suggesting that cytosolic calcium may regulate the expression of this proap optotic protein. Furthermore, ectopic expression of Hrk induced cell death of hematopoietic progenitors in the presence of IL-3, Thus, Hrk is specific ally and rapidly induced in hematopoietic progenitors after growth factor d eprivation or treatment with chemotherapeutic drugs, and this may be suffic ient to induce apoptosis in these cells. (Biood, 2000;95:2742-2147) (C) 200 0 by The American Society of Hematology.